RESUMEN
Microdosing ketamine is a novel antidepressant for treatment-resistant depression. Traditional antidepressants, like selective serotonin reuptake inhibitors (SSRIs), inhibit serotonin reuptake, but it is not clear if ketamine shows a similar mechanism. Here, we tested the effects of feeding ketamine and SSRIs to Drosophila melanogaster larvae, which has a similar serotonin system to mammals and is a good model to track depressive behaviors, such as locomotion and feeding. Fast-scan cyclic voltammetry (FSCV) was used to measure optogenetically stimulated serotonin changes, and locomotion tracking software and blue dye feeding to monitor behavior. We fed larvae various doses (1-100 mM) of antidepressants for 24 h and found that 1 mM ketamine did not affect serotonin, but increased locomotion and feeding. Low doses (≤10 mM) of escitalopram and fluoxetine inhibited dSERT and also increased feeding and locomotion behaviors. At 100 mM, ketamine inhibited dSERT and increased serotonin concentrations, but decreased locomotion and feeding because of its anesthetic properties. Since microdosing ketamine causes behavioral effects, we further investigated behavioral changes with a SERT16 mutant and low doses of other NMDA receptor antagonists and 5-HT1A and 2 agonists. Feeding and locomotion changes were similar to ketamine in the mutant, and we found NMDA receptor antagonism increased feeding, while serotonin receptor agonism increased locomotion, which could explain these effects with ketamine. Ultimately, this work shows that Drosophila is a good model to discern antidepressant mechanisms, and that ketamine does not work on dSERT like SSRIs, but effects behavior with other mechanisms that should be investigated further.
Asunto(s)
Drosophila melanogaster , Ketamina , Locomoción , Receptores de Serotonina , Inhibidores Selectivos de la Recaptación de Serotonina , Animales , Ketamina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Receptores de Serotonina/metabolismo , Receptores de Serotonina/efectos de los fármacos , Locomoción/efectos de los fármacos , Receptores de Glutamato/metabolismo , Receptores de Glutamato/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Serotonina/metabolismo , Conducta Alimentaria/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Larva , Fluoxetina/farmacología , Antidepresivos/farmacologíaRESUMEN
Parkinson's disease (PD) is the second-most prevalent central nervous system (CNS) neurodegenerative condition. Over the past few decades, suppression of BCR-Abelson tyrosine kinase (c-Abl), which serves as a marker of -synuclein aggregation and oxidative stress, has shown promise as a potential therapy target in PD. c-Abl inhibition has the potential to provide neuroprotection against PD, as shown by experimental results and the first-in-human trial, which supports the strategy in bigger clinical trials. Furthermore, glutamate receptors have also been proposed as potential therapeutic targets for the treatment of PD since they facilitate and regulate synaptic neurotransmission throughout the basal ganglia motor system. It has been noticed that pharmacological manipulation of the receptors can change normal as well as abnormal neurotransmission in the Parkinsonian brain. The review study contributes to a comprehensive understanding of the approach toward the role of c-Abl and glutamate receptors in Parkinson's disease by highlighting the significance and urgent necessity to investigate new pharmacotherapeutic targets. The article covers an extensive insight into the concept of targeting, pathophysiology, and c-Abl interaction with α-synuclein, parkin, and cyclin-dependent kinase 5 (Cdk5). Furthermore, the concepts of Nmethyl- D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPA) receptor, and glutamate receptors are discussed briefly. Conclusion: This review article focuses on in-depth literature findings supported by an evidence-based discussion on pre-clinical trials and clinical trials related to c-Abl and glutamate receptors that act as potential therapeutic targets for PD.
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Enfermedad de Parkinson , Proteínas Proto-Oncogénicas c-abl , Receptores de Glutamato , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-abl/metabolismo , Receptores de Glutamato/metabolismo , Receptores de Glutamato/efectos de los fármacos , Animales , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
A series of Special Issues of Neuropharmacology celebrates the 40th anniversary of a seminal review on excitatory amino acid (EAA) receptors by two pioneers of the field - Dick Evans and Jeff Watkins. Brought together in the Department of Pharmacology at the University of Bristol in the 1970s, they forged a partnership that, through the synthetic chemistry prowess of Jeff Watkins, which provided novel agonists and antagonists for EAA receptors for Dick Evans's deft experimental studies, generated enormous insight into the multitude of actions of EAAs in the nervous system. Among many achievements from this time was not just the naming of the N-methyl-d-aspartate (NMDA) receptor, but also the demonstration of its antagonism by magnesium ions. Here, Dick and Jeff reflect upon those early halcyon days of EAA research, which, as these six1 Special Issues of Neuropharmacology demonstrate, is very much alive and kicking. Bruno G. Frenguelli, Editor-in-Chief, Neuropharmacology.
Asunto(s)
Aminoácidos Excitadores/historia , Neurofarmacología/historia , Receptores de Glutamato/historia , Animales , Antagonistas de Aminoácidos Excitadores , Historia del Siglo XX , Humanos , Receptores de Glutamato/efectos de los fármacos , Investigación , Reino Unido , UniversidadesRESUMEN
In 1981 Jeff Watkins and Dick Evans wrote what was to become a seminal review on excitatory amino acids (EAAs) and their receptors (Watkins and Evans, 1981). Bringing together various lines of evidence dating back over several decades on: the distribution in the nervous system of putative amino acid neurotransmitters; enzymes involved in their production and metabolism; the uptake and release of amino acids; binding of EAAs to membranes; the pharmacological action of endogenous excitatory amino acids and their synthetic analogues, and notably the actions of antagonists for the excitations caused by both nerve stimulation and exogenous agonists, often using pharmacological tools developed by Jeff and his colleagues, they provided a compelling account for EAAs, especially l-glutamate, as a bona fide neurotransmitter in the nervous system. The rest, as they say, is history, but far from being consigned to history, EAA research is in rude health well into the 21st Century as this series of Special Issues of Neuropharmacology exemplifies. With EAAs and their receptors flourishing across a wide range of disciplines and clinical conditions, we enter into a dialogue with two of the most prominent and influential figures in the early days of EAA research: Jeff Watkins and Dick Evans.
Asunto(s)
Aminoácidos Excitadores/fisiología , Neurotransmisores/fisiología , Receptores de Glutamato/fisiología , Animales , Aminoácidos Excitadores/farmacología , Humanos , Receptores de Glutamato/efectos de los fármacos , Sinapsis/fisiologíaRESUMEN
T cells of aged people, and of patients with either cancer or severe infections (including COVID-19), are often exhausted, senescent and dysfunctional, leading to increased susceptibilities, complications and mortality. Neurotransmitters and Neuropeptides bind their receptors in T cells, and induce multiple beneficial T cell functions. Yet, T cells of different people vary in the expression levels of Neurotransmitter and Neuropeptide receptors, and in the magnitude of the corresponding effects. Therefore, we performed an individual-based study on T cells of 3 healthy subjects, and 3 Hepatocellular Carcinoma (HCC) patients. HCC usually develops due to chronic inflammation. The inflamed liver induces reduction and inhibition of CD4+ T cells and Natural Killer (NK) cells. Immune-based therapies for HCC are urgently needed. We tested if selected Neurotransmitters and Neuropeptides decrease the key checkpoint protein PD-1 in human T cells, and increase proliferation and killing of HCC cells. First, we confirmed human T cells express all dopamine receptors (DRs), and glutamate receptors (GluRs): AMPA-GluR3, NMDA-R and mGluR. Second, we discovered that either Dopamine, Glutamate, GnRH-II, Neuropeptide Y and/or CGRP (10nM), as well as DR and GluR agonists, induced the following effects: 1. Decreased significantly both %PD-1+ T cells and PD-1 expression level per cell (up to 60% decrease, within 1 h only); 2. Increased significantly the number of T cells that proliferated in the presence of HCC cells (up to 7 fold increase), 3. Increased significantly T cell killing of HCC cells (up to 2 fold increase). 4. Few non-conventional combinations of Neurotransmitters and Neuropeptides had surprising synergistic beneficial effects. We conclude that Dopamine, Glutamate, GnRH-II, Neuropeptide Y and CGRP, alone or in combinations, can decrease % PD-1+ T cells and PD-1 expression per cell, in T cells of both healthy subjects and HCC patients, and increase their proliferation in response to HCC cells and killing of HCC cells. Yet, testing T cells of many more cancer patients is absolutely needed. Based on these findings and previous ones, we designed a novel "Personalized Adoptive Neuro-Immunotherapy", calling for validation of safety and efficacy in clinical trials.
Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Proliferación Celular/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neuropéptidos/farmacología , Neurotransmisores/farmacología , Receptor de Muerte Celular Programada 1/biosíntesis , Receptor de Muerte Celular Programada 1/genética , Linfocitos T/metabolismo , Linfocitos T CD4-Positivos/metabolismo , COVID-19/complicaciones , Carcinoma Hepatocelular/patología , Dopamina/farmacología , Agonistas de Dopamina/farmacología , Humanos , Inmunoterapia , Células Asesinas Naturales/metabolismo , Neoplasias Hepáticas/patología , Receptores de Glutamato/efectos de los fármacos , Receptores de Neuropéptido/metabolismo , Receptores de Neurotransmisores/metabolismoRESUMEN
Loss-of-function mutations in progranulin (GRN) are a major genetic cause of frontotemporal dementia (FTD), possibly due to loss of progranulin's neurotrophic and anti-inflammatory effects. Progranulin promotes neuronal growth and protects against excitotoxicity and other forms of injury. It is unclear if these neurotrophic effects are mediated through cellular signaling or through promotion of lysosomal function. Progranulin is a secreted proprotein that may activate neurotrophic signaling through cell-surface receptors. However, progranulin is efficiently trafficked to lysosomes and is necessary for maintaining lysosomal function. To determine which of these mechanisms mediates progranulin's protection against excitotoxicity, we generated lentiviral vectors expressing progranulin (PGRN) or lysosome-targeted progranulin (L-PGRN). L-PGRN was generated by fusing the LAMP-1 transmembrane and cytosolic domains to the C-terminus of progranulin. L-PGRN exhibited no detectable secretion, but was delivered to lysosomes and processed into granulins. PGRN and L-PGRN protected against NMDA excitotoxicity in rat primary cortical neurons, but L-PGRN had more consistent protective effects than PGRN. L-PGRN's protective effects were likely mediated through the autophagy-lysosomal pathway. In control neurons, an excitotoxic dose of NMDA stimulated autophagy, and inhibiting autophagy with 3-methyladenine reduced excitotoxic cell death. L-PGRN blunted the autophagic response to NMDA and occluded the protective effect of 3-methyladenine. This was not due to a general impairment of autophagy, as L-PGRN increased basal autophagy and did not alter autophagy after nutrient starvation. These data show that progranulin's protection against excitotoxicity does not require extracellular progranulin, but is mediated through lysosomes, providing a mechanistic link between progranulin's lysosomal and neurotrophic effects.
Asunto(s)
Lisosomas/metabolismo , Neuronas/metabolismo , Progranulinas/administración & dosificación , Receptores de Glutamato/efectos de los fármacos , Animales , Ratas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
The efficacy of standard antidepressants is limited for many patients with mood disorders such as major depressive disorder (MDD) and bipolar depression, underscoring the urgent need to develop novel therapeutics. Both clinical and preclinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders. In particular, rapid reductions in depressive symptoms have been observed in response to subanesthetic doses of the glutamatergic modulator racemic (R,S)-ketamine in individuals with mood disorders. These results have prompted investigation into other glutamatergic modulators for depression, both as monotherapy and adjunctively. Several glutamate receptor-modulating agents have been tested in proof-of-concept studies for mood disorders. This manuscript gives a brief overview of the glutamate system and its relevance to rapid antidepressant response and discusses the existing clinical evidence for glutamate receptor-modulating agents, including (1) broad glutamatergic modulators ((R,S)-ketamine, esketamine, (R)-ketamine, (2R,6R)-hydroxynorketamine [HNK], dextromethorphan, Nuedexta [a combination of dextromethorphan and quinidine], deudextromethorphan [AVP-786], axsome [AXS-05], dextromethadone [REL-1017], nitrous oxide, AZD6765, CLE100, AGN-241751); (2) glycine site modulators (D-cycloserine [DCS], NRX-101, rapastinel [GLYX-13], apimostinel [NRX-1074], sarcosine, 4-chlorokynurenine [4-Cl-KYN/AV-101]); (3) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (eliprodil [EVT-101], traxoprodil [CP-101,606], rislenemdaz [MK-0657/CERC-301]); (4) metabotropic glutamate receptor (mGluR) modulators (basimglurant, AZD2066, RG1578, TS-161); and (5) mammalian target of rapamycin complex 1 (mTORC1) activators (NV-5138). Many of these agents are still in the preliminary stages of development. Furthermore, to date, most have demonstrated relatively modest effects compared with (R,S)-ketamine and esketamine, though some have shown more favorable characteristics. Of these novel agents, the most promising, and the ones for which the most evidence exists, appear to be those targeting ionotropic glutamate receptors.
Asunto(s)
Fármacos actuantes sobre Aminoácidos Excitadores/uso terapéutico , Trastornos del Humor/tratamiento farmacológico , Receptores de Glutamato/efectos de los fármacos , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/fisiopatología , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/fisiopatología , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Ácido Glutámico/metabolismo , Humanos , Trastornos del Humor/fisiopatología , Receptores de Glutamato/metabolismoRESUMEN
Increasing evidence indicates that dysfunction of glutamate receptors is involved in the pathophysiology of major depressive disorder (MDD). Although accumulating efforts have been made to elucidate the applications and mechanisms underlying antidepressant-like effects of ketamine, a non-selective antagonist of N-methyl-d-aspartate receptor (NMDAR), the role of specific glutamate receptor subunit in regulating depression is not completely clear. The current review aims to discuss the relationships between glutamate receptor subunits and depressive-like behaviors. Research literatures were searched from inception to July 2020. We summarized the alterations of glutamate receptor subunits in patients with MDD and animal models of depression. Animal behaviors in response to dysfunction of glutamate receptor subunits were also surveyed. To fully understand mechanisms underlying antidepressant-like effects of modulators targeting glutamate receptors, we discussed effects of each glutamate receptor subunit on serotonin system, synaptic plasticity, neurogenesis and neuroinflammation. Finally, we collected most recent clinical applications of glutamate receptor modulators and pointed out the limitations of these candidates in the treatment of MDD.
Asunto(s)
Antidepresivos , Trastorno Depresivo Mayor , Receptores de Glutamato , Animales , Antidepresivos/farmacología , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/fisiopatología , Desarrollo de Medicamentos , Humanos , Receptores de Glutamato/efectos de los fármacos , Receptores de Glutamato/fisiologíaRESUMEN
Bisphenol A (BPA), a component of polycarbonate and epoxy resins, has been reported to induce learning and memory deficits. However, the mechanisms have not been fully elucidated. Growing evidence has suggested that N-methyl-d-aspartate receptors (NMDARs) are involved in cognitive impairments. In this study, BPA was administered to female Sprague-Dawley rats (six per dose group) at concentrations of 0 (control), 4, 40, and 400 µg/kg·body weight/day from gestation day 1 through lactation day 21. Spatial learning was evaluated using the Morris water maze on postnatal day 22. Expression levels of NMDARs were determined using real-time polymerase chain reaction and Western blot. The results showed that male offspring exposed to BPA exhibited increased latency in reaching the platform and reduced time in the target quadrant, and the number of crossing the platform was less, as compared with the control group. The mRNA and protein expression levels of NMDARs in the hippocampus were significantly downregulated when compared with the control group of male offspring. The data showed that maternal exposure to BPA at low dosage can cause cognitive deficits in male rat offspring, probably due to a decrease in NMDARs in the hippocampus.
Asunto(s)
Compuestos de Bencidrilo/toxicidad , Trastornos de la Memoria/inducido químicamente , Fenoles/toxicidad , Efectos Tardíos de la Exposición Prenatal , Receptores de Glutamato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Adulto , Animales , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Modelos Animales , Embarazo , Ratas , Ratas Sprague-Dawley , Factores SexualesRESUMEN
BACKGROUND: Although extensively studied, the effect of antipsychotics is not completely understood at a network level. We tested the hypothesis that acute administration of haloperidol would modulate functional connectivity of brain regions relevant to schizophrenia pathophysiology. To assess putative changes in brain network properties and regional interactivity, we studied the expression of Homer1a, an Immediate Early Gene (IEG) demonstrated to be induced by antipsychotic administration and coding for a protein involved in glutamatergic synapses remodeling. METHODS: Sprague-Dawley rats (n = 26) assigned to vehicle (VEH; NaCl 0.9%) or haloperidol (HAL; 0.8 mg/kg) were included in the network analysis. Homer1a mRNA induction was evaluated by in situ hybridization. Signal intensity analysis was performed in 33 Regions of Interest (ROIs) in the cortex, the caudate putamen, and the nucleus accumbens. A signal correlation analysis was performed, computing all possible pairwise Pearson correlations among ROIs in the two groups. Two networks were generated for HAL and VEH groups, and their properties and topography were explored. RESULTS: VEH and HAL networks showed qualitative differences in global efficiency and clustering coefficient. The HAL network showed enhanced interactivity between cortical and striatal regions, and within caudate putamen subdivisions. On the other hand, it exhibited reduced inter-correlations between cingulate cortex and anterior insula and caudate putamen and nucleus accumbens. Moreover, haloperidol was able to modulate centrality of crucial functional hubs. These preclinical results corroborate and expand the clinical evidence that antipsychotics may modulate specific brain network properties and disease-related circuits' interactivity.
Asunto(s)
Redes Reguladoras de Genes/efectos de los fármacos , Genes Inmediatos-Precoces/efectos de los fármacos , Haloperidol/farmacología , Red Nerviosa/efectos de los fármacos , Densidad Postsináptica/efectos de los fármacos , Receptores de Glutamato/efectos de los fármacos , Animales , Antipsicóticos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Hibridación in Situ , Masculino , Vías Nerviosas/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sinapsis/efectos de los fármacos , TranscriptomaRESUMEN
Although melamine exposure induces cognitive deficits and dysfunctional neurotransmission in hippocampal Cornus Ammonis (CA) 1 region of rats, it is unclear whether the neural function, such as neural oscillations between hippocampal CA3-CA1 pathway and postsynaptic receptors involves in these effects. The levels of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit glutamate receptor (GluR) 1 and GluR2/3 in CA1 region of melamine-treated rats, which were intragastric treated with 300 mg/kg/day for 4 weeks, were detected. Following systemic or intra-hippocampal CA1 injection with GluR2/3 agonist, spatial learning of melamine-treated rats was assessed in Morris water maze (MWM) task. Local field potentials were recorded in CA3-CA1 pathway before and during behavioral test. General Partial Directed Coherence approach was applied to determine directionality of neural information flow between CA3 and CA1 regions. Results showed that melamine exposure reduced GluR2/3 but not GluR1 level and systemic or intra-hippocampal CA1 injection with GluR2/3 agonist effectively mitigated the learning deficits. Phase synchronization between CA3 and CA1 regions were significantly diminished in delta, theta and alpha oscillations. Coupling directional index and strength of CA3 driving CA1 were marked reduced as well. Intra-hippocampal CA1 infusion with GluR2/3 agonist significantly enhanced the phase locked value and reversed the melamine-induced reduction in the neural information flow (NIF) from CA3 to CA1 region. These findings support that melamine exposure decrease the expression of GluR2/3 subunit involved in weakening directionality index of NIF, and thereby induced spatial learning deficits.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Hipocampo/efectos de los fármacos , Vías Nerviosas/efectos de los fármacos , Receptores AMPA/metabolismo , Receptores de Glutamato/efectos de los fármacos , Receptores de Glutamato/metabolismo , Triazinas/toxicidad , Animales , Humanos , Masculino , Modelos Animales , Ratas , Ratas Endogámicas WFRESUMEN
RATIONALE: There is increasing concern regarding the use of selective serotonin reuptake inhibitors (SSRIs) in pregnancy. Animal studies repeatedly show increased anxiety- and depressive-like behaviours in offspring exposed perinatally to SSRIs, however much of this research is in male offspring. OBJECTIVES: The primary aim of this study was to investigate the effects of perinatal SSRI exposure on emotionality-related behaviours in female offspring and associated glutamatergic markers, in Sprague-Dawley (SD) rats and in the Wistar-Kyoto (WKY) rat model of depression. Secondly, we sought to investigate the glutamatergic profile of female WKY rats that may underlie their depressive- and anxiety-like phenotype. METHODS: WKY and SD rat dams were treated with the SSRI, fluoxetine (FLX; 10 mg/kg/day), or vehicle, throughout gestation and lactation (5 weeks total). Female adolescent offspring underwent behaviour testing followed by quantitative immunoblot of glutamatergic markers in the prefrontal cortex and ventral hippocampus. RESULTS: Naïve female WKY offspring displayed an anxiety-like and depressive-like phenotype as well as reductions in NMDA and AMPA receptor subunits and PSD-95 in both ventral hippocampus and prefrontal cortex, compared to SD controls. Perinatal FLX treatment increased anxiety-like and forced swim immobility behaviours in SD offspring but did not influence behaviour in female WKY offspring using these tests. Perinatal FLX exposure did not influence NMDA or AMPA receptor subunit expression in female WKY or SD offspring; it did however have restricted effects on group I mGluR expression in SD and WKY offspring and reduce the glutamatergic synaptic scaffold, PSD-95. CONCLUSION: These findings suggest female offspring of the WKY strain display deficits in glutamatergic markers which may be related to their depressive- and anxiety-like phenotype. While FLX exposed SD offspring displayed increases in anxiety-like and depressive-like behaviours, further studies are needed to assess the potential impact of developmental FLX exposure on the behavioural phenotype of female WKY rats.
Asunto(s)
Hipocampo/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Pirimidinas/farmacología , Receptores de Glutamato/efectos de los fármacos , Animales , Animales Recién Nacidos , Ansiedad/tratamiento farmacológico , Trastorno Depresivo/tratamiento farmacológico , Modelos Animales de Enfermedad , Prueba de Laberinto Elevado , Femenino , Hipocampo/química , Corteza Prefrontal/química , Ratas , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Receptores de Glutamato/análisisRESUMEN
PURPOSE: To explore genistein, the most active component of soy isoflavones, on viability, expression of estrogen receptor (ER) subtypes, choline acetyltransferase (ChAT), and glutamate receptor subunits in amyloid peptide 25-35-induced hippocampal neurons, providing valuable data and basic information for neuroprotective effect of genistein in Aß25-35-induced neuronal injury. METHODS: We established an in vitro model of Alzheimer's disease by exposing primary hippocampal neurons of newborn rats to amyloid peptide 25-35 (20 µM) for 24 h and observing the effects of genistein (10 µM, 3 h) on viability, expression of ER subtypes, ChAT, NMDA receptor subunit NR2B and AMPA receptor subunit GluR2 in Aß25-35-induced hippocampal neurons. RESULTS: We found that amyloid peptide 25-35 exposure reduced the viability of hippocampal neurons. Meanwhile, amyloid peptide 25-35 exposure decreased the expression of ER subtypes, ChAT and GluR2, and increased the expression of NR2B. Genistein at least partially reversed the effects of amyloid peptide 25-35 in hippocampal neurons. CONCLUSION: Genistein could increase the expression of ChAT as a consequence of activating estrogen receptor subtypes, modulating the expression of NR2B and GluR2, and thereby ameliorating the status of hippocampal neurons and exerting neuroprotective effects against amyloid peptide 25-35. Our data suggest that genistein might represent a potential cell-targeted therapy which could be a promising approach to treating AD.
Asunto(s)
Péptidos beta-Amiloides/antagonistas & inhibidores , Muerte Celular/fisiología , Colina O-Acetiltransferasa/antagonistas & inhibidores , Genisteína/farmacología , Neuronas/efectos de los fármacos , Fragmentos de Péptidos/antagonistas & inhibidores , Receptores de Estrógenos/efectos de los fármacos , Receptores de Glutamato/efectos de los fármacos , Péptidos beta-Amiloides/fisiología , Animales , Neuronas/citología , Neuronas/enzimología , Neuronas/metabolismo , Fragmentos de Péptidos/fisiología , Ratas , Ratas WistarRESUMEN
Glutamatergic AMPA and NMDA receptors in the ventral tegmental area (VTA) are central for cocaine first exposure and posterior craving maintenance. However, the exact rules that coordinate the synaptic dynamics of these receptors in dopaminergic VTA neurons and behavioral outcomes are poorly understood. Additionally, synaptic homeostatic plasticity is present in response to chronic excitability changes in neuronal circuits, adjusting the strength of synapses to stabilize the firing rate. Despite having correspondent mechanisms, little is known about the relationship between continuous cocaine exposure and homeostatic synaptic changes in the VTA neurons. Here, we assess the role of homeostatic mechanisms in the neurobiology of cocaine addiction by providing a brief overview of the parallels between cocaine-induced synaptic potentiation and long-term synaptic adaptations, focusing on the regulation of GluA1- and GluN1- containing receptors.
Asunto(s)
Trastornos Relacionados con Cocaína/fisiopatología , Cocaína/farmacología , Homeostasis/efectos de los fármacos , Receptores de Glutamato/efectos de los fármacos , Receptores de Glutamato/metabolismo , Sinapsis/efectos de los fármacos , Animales , Humanos , Potenciación a Largo Plazo/efectos de los fármacos , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Plasticidad Neuronal , Ratas , Receptores AMPA/biosíntesis , Receptores AMPA/genética , Receptores de N-Metil-D-Aspartato/biosíntesis , Receptores de N-Metil-D-Aspartato/genéticaRESUMEN
Chronic glutamate excitotoxicity has been thought to be involved in numerous neurodegenerative disorders. A small but significant loss of membrane cholesterol has been reported following a short stimulation of ionotropic glutamate receptors (iGluRs). We investigated the alteration of brain cholesterol following chronic glutamate treatment. The alteration of cholesterol levels was evaluated in the hippocampus from the adult rats that received the subcutaneous injection with monosodium l-glutamate at 1, 3, 5, and 7 days of age. The regulation of CYP46A1, LXRα, and ApoE levels were assayed following subtoxic glutamate treatment in SH-SY5Y cells as well as HT-22 cells lacking iGluRs. The ratio of 24S-hydroxycholesterol to cholesterol was elevated in the adult rats exposed to monosodium l-glutamate before the weaning age, compared to the control. The blockers of NMDA receptor (MK801) and mGluR5 (MPEP) attenuated the glutamate-induced loss of cholesterol and elevation of 24S-hydroxycholesterol level in SH-SY5Y cells. The induction of the mRNA levels of CYP46A1, LXRα, and ApoE by glutamate was observed in both SH-SY5Y cells and HT-22 cells; additionally, MK801 and MPEP attenuated the increases in these genes in SH-SY5Y cells. The increase in the binding of LXRα proteins with ApoE promoter following glutamate treatment was attenuated by MK801. The luciferase assay indicated the binding of CREB protein with CYP46A1 promoter, and the glutamate-induced CREB expression was inhibited by MK801. The results suggest that glutamate, the major excitatory neurotransmitter, may affect the metabolism and redistribution of cholesterol in the neuronal cells via its specific receptors during chronic exposure.
Asunto(s)
Apolipoproteínas E/biosíntesis , Química Encefálica/efectos de los fármacos , Colesterol 24-Hidroxilasa/biosíntesis , Colesterol/metabolismo , Glutamato de Sodio/farmacología , Animales , Línea Celular , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Homeostasis , Receptores X del Hígado/antagonistas & inhibidores , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Glutamato/efectos de los fármacos , Receptores de Ácido Kaínico/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The inflammatory hypothesis is one of the most important mechanisms of depression. Fucoidan is a bioactive sulfated polysaccharide abundant in brown seaweeds with anti-inflammatory activity. However, the antidepressant effects of fucoidan on chronic stress-induced depressive-like behaviors have not been well elucidated. Here, we used two different depressive-like mouse models, lipopolysaccharide (LPS) and chronic restraint stress (CRS) models, to explore the detailed molecular mechanism underlying its antidepressant-like effects in C57BL/6J mice by combining multiple behavioral, molecular and immunofluorescence experiments. Adenovirus-mediated overexpression of caspase-1 and pharmacological inhibitors were also used to clarify the antidepressant mechanisms of fucoidan. We found that acute administration of fucoidan did not produce antidepressant effects in the tail suspension test (TST) and forced swim test (FST). Interestingly, chronic fucoidan administration not only dose-dependently reduced stress-induced depressive-like behaviors in the TST, FST, sucrose preference test (SPT), and novelty-suppressed feeding test (NSFT), but also alleviated the downregulation of brain-derived neurotrophic factor (BDNF)-dependent synaptic plasticity via inhibiting caspase-1-mediated inflammation in the hippocampus of mice. Moreover, fucoidan significantly ameliorated behavioral and synaptic plasticity abnormalities in the overexpression of caspase-1 in the hippocampus of mice. Furthermore, blocking BDNF abolished the antidepressant-like effects of fucoidan in mice. Therefore, our findings clearly indicate that fucoidan provides a potential supplementary noninvasive treatment for depression by inhibition of hippocampal inflammation.
Asunto(s)
Polisacáridos/farmacología , Receptores de Glutamato/efectos de los fármacos , Animales , Antidepresivos/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Hipocampo/patología , Inflamación/tratamiento farmacológico , Inflamación/prevención & control , Ratones , Ratones Endogámicos C57BL , Polisacáridos/uso terapéuticoRESUMEN
Chronic cerebral hypoperfusion is an important risk factor for vascular dementia (VaD) and other brain dysfunctions, for which there are currently no effective medications available. In the present study, we investigated the potential therapeutic effects of cornel iridoid glycoside (CIG) on VaD in rats modeled by permanent bilateral common carotid artery ligation (2-vessel occlusion, 2VO). The object recognition test (ORT) and Morris water maze (MWM) test were conducted to evaluate the learning and memory function. Western blot analysis and immunohistochemical staining were used to detect the expression of related proteins. Results showed that intragastric administration of CIG (30, 60, and 120â¯mg/kg) for 3 months significantly increased the discrimination index in ORT and decreased the escape latency in MWM test, ameliorating the learning and memory deficit in 2VO rats. Further data indicated that CIG increased the expression of neurotrophic factors (NGF and BDNF) and their receptors (TrkA and TrkB), glutamate receptor subunits (NMDAR1 and GluR2) in the cerebral cortex and hippocampus of 2VO rats. In addition, CIG elevated the expression of PI3K subunits p110α and p85, further upregulated the phosphorylation of Akt, GSK3ß-ser9 and CREB in the cerebral cortex and hippocampus at 3 months after 2VO surgery. Collectively, CIG treatment improved learning and memory deficit induced by chronic cerebral hypoperfusion via increasing neurotrophic factors thus protecting glutamate receptors and activating PI3K/Akt/GSK3ß/CREB signaling pathway in rats. These results suggest that CIG may be beneficial to VaD therapy.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Cornaceae , Demencia Vascular/tratamiento farmacológico , Glicósidos Iridoides/farmacología , Aprendizaje/efectos de los fármacos , Factores de Crecimiento Nervioso/efectos de los fármacos , Receptores de Glutamato/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Disfunción Cognitiva/etiología , Demencia Vascular/complicaciones , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Glicósidos Iridoides/administración & dosificación , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
There is a growing interest in new molecular targets for antipsychotic therapy. Multiple signal transduction systems have been recently implicated in the pathophysiology of schizophrenia. However, the weight of each specific mechanism remains controversial. A need for a more vigorous approach to the pharmacotherapy of schizophrenia arises from the bedside: about 30-40% of patients do not respond to antipsychotic therapy. Postsynaptic Density (PSD) proteins have recently attracted attention for their role in signal transduction modulation and for their potential implication in psychosis and cognition. The involvement of PSD in the pathophysiology of schizophrenia is supported by post mortem studies, preclinical animal models, modulation by antipsychotics, and association of PSD genes with schizophrenia in GWAS. Taken together, these studies underline the role of PSD modulation, its effects on striatal function and its relationship with motor, executive- and cognitive-like functions suggesting a potential role of PSD proteins as a l target of novel intervention in the treatment of refractory psychosis.
Asunto(s)
Antipsicóticos/uso terapéutico , Densidad Postsináptica/efectos de los fármacos , Receptores de Glutamato/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Investigación Biomédica Traslacional , Animales , Antipsicóticos/farmacología , Humanos , Proteínas del Tejido Nervioso , Receptores de N-Metil-D-Aspartato/efectos de los fármacosRESUMEN
BACKGROUND: Binge drinking is a pattern of alcohol intake characterized by excessive and intermittent alcohol consumption over a very short period of time that is more used during adolescence. We aim to compare the lasting effects of a chronic-moderate vs. this intermittent-excessive way of alcohol intake during adolescence in spatial memory and in the expression of glutamatergic receptors and GSK3ß activity. METHODS: Adolescent male Wistar rats were given ethanol/saline i.p. injections in four different groups: High-I (4 g/kg of a 25% (vol/vol) every 3 days), Low-I (1 g/kg of a 5% (vol/vol) every 3 days), M (0.3 g/kg of a 2.5% (vol/vol) daily) and Control (C, sterile isotonic saline daily). Rats received ethanol for up to five 3-day cycles. Spatial memory was measured by spontaneous alternation in the Y-Maze. Gene and protein expression of hippocampal proteins were also analysed. RESULTS: Both high- and low-intermittent ethanol administration produced spatial memory impairment and changes in glutamatergic receptors gene expression were observed regardless of the pattern of exposure. High doses of intermittent alcohol administration produced an increase of phosphorylation of GSK3ß Ser9. Moreover, moderate alcohol administration produced a down-regulation of the AMPAR 2/3 ratio despite lack of spatial memory deficits. CONCLUSIONS: Excessive and intermittent ethanol exposure during adolescence impaired the spatial memory processes during adulthood regardless of the amount of alcohol administered. Moreover, chronic-moderate and intermittent pattern induced changes in the expression of glutamatergic receptors. In addition, high-intermittent ethanol exposure during adolescence inactivated GSK3ß by increasing its phosphorylation in Ser9.
Asunto(s)
Etanol/efectos adversos , Hipocampo/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Consumo de Bebidas Alcohólicas , Animales , Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Tolerancia a Medicamentos , Etanol/metabolismo , Etanol/farmacología , Expresión Génica/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hipocampo/metabolismo , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/etiología , Ratas , Ratas Wistar , Receptores de Glutamato/efectos de los fármacos , Receptores de Glutamato/metabolismoRESUMEN
Drugs of abuse induce widespread synaptic adaptations in the mesolimbic dopamine (DA) neurons. Such drug-induced neuroadaptations may constitute an initial cellular mechanism eventually leading to compulsive drug-seeking behavior. To evaluate the impact of GABAB receptors on addiction-related persistent neuroplasticity, we tested the ability of orthosteric agonist baclofen and two positive allosteric modulators (PAMs) of GABAB receptors to suppress neuroadaptations in the ventral tegmental area (VTA) and reward-related behaviors induced by ethanol and cocaine. A novel compound (S)-1-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-4-methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (ORM-27669) was found to be a GABAB PAM of low efficacy as agonist, whereas the reference compound (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) had a different allosteric profile being a more potent PAM in the calcium-based assay and an agonist, coupled with potent PAM activity, in the [35 S] GTPγS binding assay in rat and human recombinant receptors. Using autoradiography, the high-efficacy rac-BHFF and the low-efficacy ORM-27669 potentiated the effects of baclofen on [35 S] GTPγS binding with identical brain regional distribution. Treatment of mice with baclofen, rac-BHFF, or ORM-27669 failed to induce glutamate receptor neuroplasticity in the VTA DA neurons. Pretreatment with rac-BHFF at non-sedative doses effectively reversed both ethanol- and cocaine-induced plasticity and attenuated cocaine i.v. self-administration and ethanol drinking. Pretreatment with ORM-27669 only reversed ethanol-induced neuroplasticity and attenuated ethanol drinking but had no effects on cocaine-induced neuroplasticity or self-administration. These findings encourage further investigation of GABAB receptor PAMs with different efficacies in addiction models to develop novel treatment strategies for drug addiction.